CA2469076A1 - Pharmaceutical compositions comprising dihydropyridinone compounds and an immunoregulatory or an antiinflammatory agent and their uses - Google Patents

Pharmaceutical compositions comprising dihydropyridinone compounds and an immunoregulatory or an antiinflammatory agent and their uses Download PDF

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CA2469076A1
CA2469076A1 CA002469076A CA2469076A CA2469076A1 CA 2469076 A1 CA2469076 A1 CA 2469076A1 CA 002469076 A CA002469076 A CA 002469076A CA 2469076 A CA2469076 A CA 2469076A CA 2469076 A1 CA2469076 A1 CA 2469076A1
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CA2469076C (en
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Terence Smith
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Eisai R&D Management Co Ltd
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

The present invention relates to compositions comprising 1,2-dihydropyridin-2-one compounds and an immunoregulatory or anti-inflammatory agent. The compositions are useful for the prevention or the treatment of neurodegenerative diseases, for example demyelinating disorders.

Claims (28)

1. A composition comprising I) a compound represented by the following formula, a salt thereof or a hydrate thereof:
wherein, Q indicates NH, O or S; and R1, R2, R3, R4 and R5 are the same as or different from each other and each indicates hydrogen atom, a halogen atom, a C1-6 alkyl group or a group represented by the formula -X-A (wherein X indicates a single bond, an optionally substituted C1-6 alkylene group an optionally substituted C2-6 alkenylene group, an optionally substituted C2-6 alkynylene group, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-CO-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(R11)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)p-, -S(O)q-CH2-, -CH2-O-, -O-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16)- (wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 indicate hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group; and m, n, p and q indicates an integer of 0, 1 or 2 independently); and A indicates a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a 5 to 14 membered non-aromatic heterocyclic group, a C6-14 aromatic hydrocarbocyclic group, or a 5 to 14 membered aromatic heterocyclic group which may be substituted respectively, provided that 3 groups among R1, R2, R3, R4 and R5 are always the same as or different from each other and each indicates -X-A;
and the residual 2 groups always indicate hydrogen atom, a halogen atom or a C1-6 alkyl group); and II) an immunomodulatory, immunosuppressive, or an anti-inflammatory agent.
2. A composition, as claimed in claim 1, wherein the compound is a salt thereof or hydrates thereof, which is represented by the formula:

wherein Q indicates NH, O or S; X1, X2 and X3 are the same as or different from each other and each indicates a single bond, an optionally substituted C1-6 alkylene group, an optionally substituted C2-6 alkenylene group, an optionally substituted C2-6 alkynylene group, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-CO-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(R11)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)p-, -S(O)q-CH2-, -CH2-O-, -O-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16)-(wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 indicate hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group; and m, n, p and q are independent of each other and each indicates an integer of 0, 1 or 2); A1, A2 and A3 are the same as or different from each other and each indicates an optionally substituted C3-8 cycloalkyl group, C3-8 cycloalkenyl group, 5 to 14-membered non-aromatic heterocyclic group, C6-14 aromatic hydrocarbocyclic group or 5 to 14-membered aromatic heterocyclic group; and R17 and R18 are the same as or different from each other and each indicates hydrogen atom, a halogen atom or a C1-6 alkyl group.
3. A composition, as claimed in claim 1 or claim 2, wherein the compound is a salt thereof or hydrates thereof, wherein X1, X2 and X3 are (1) single bond, (2) a alkylene group, a C2-6 alkenylene group or a C2-6 alkynylene group which may be optionally substituted respectively with one or more groups selected from the following substituent group a hydroxy group, a halogen atom or a cyano group, (3) -O-, (4) -S-, (5) -CO-, (6) -SO-, (7) -SO2-, (8) -N(R6)-, (9) -N(R7)-CO-, (10) -CO-N(R8)-, (11) -N(R9)-CH2-, (12) -CH2-N(R10)-, (13) -CH2-CO-, (14) -CO-CH2-, (15) -N(R11)-S(O)m-, (16) -S(O)n-N(R12)-, (17) -CH2-S(O)p-, (18) -S(O)q-CH2-, (19) -CH2-O-, (20) -O-CH2-, (21) -N(R13)-CO-N(R14)- or (22) -N(R15)-CS-N(R16)- (wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16, m, n, p and q have the same meanings as defined in the above Claim 1); and A1, A2 and A3 are a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a 5- to 14-membered non-aromatic heterocyclic group, a C6-14 aromatic hydrocarbocyclic group or a 5- to 14-membered aromatic heterocyclic group which may be optionally substituted with one or more groups selected from the following substituent group b:
the group consisting of (1) hydroxy group, (2) a halogen atom, (3) nitrite group, (4) nitro group, (5) a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group which may be optionally substituted respectively with one or more groups selected from the group consisting of hydroxy group, nitrite group, a halogen atom, a C1-6 alkylamino group, a di-(C1-6 alkyl)amino group, a C2-6 alkenylamino group, a di(C2-6 alkenylamino) group, a C2-6 alkynylamino group, a di(C2-6 alkynylamino) group, an N-C1-6 alkyl-N-C2-6 alkenylamino group, an N-C1-6 alkyl-N-C2-6 alkynylamino group, an N-C2-6 alkenyl-N-C2-6 alkynylamino group, an aralkyloxy group, a TBDMS oxy group, a C1-6 alkylsulfonylamino group, a C1-6 alkylcarbonyloxy group, a C2-6 alkenylcarbonyloxy group, a C2-6 alkynylcarbonyloxy group, an N-C1-6 alkylcarbamoyl group, an N-alkenylcarbamoyl group and an N-C1-6 alkynylcarbamoyl group, (6) a C1-6 alkoxy group, a C2-6 alkenyloxy group or a C2-6 alkynyloxy group which may be optionally substituted respectively with one or more groups selected from the group consisting of a C1-6 alkylamino group, an aralkyloxy group and hydroxy group, (7) a C1-6 alkylthio group, a C2-6 alkenylthio group or a C2-6 alkynylthio group which may be optionally substituted respectively with one or more groups selected from the group consisting of hydroxy group, nitrite group, a halogen atom, a C1-6 alkylamino group, an aralkyloxy group, a TBDMS oxy group, a C1-6 alkylsulfonylamino group, a C1-6 alkylcarbonyloxy group and a C1-6 alkylcarbamoyl group, (8) a carbonyl group substituted with a group selected from the group consisting of a C1-6 alkoxy group, amino group, a C1-6 alkylamino group, a di(C1-6 alkyl)amino group, a C2-6 alkenylamino group, a di(C2-6 alkenyl)amino group, a C2-6 alkynylamino group, a di(C2-6 alkynyl)amino group, an N-C1-6 alkyl-N-C2-6 alkenylamino group, an N-C1-6 alkyl-N-C2-6 alkynylamino group and an N-C2-6 alkenyl-N-C2-6 alkynylamino group, (9) amino group which may be optionally substituted with one or two groups selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkylsulfonyl group, a C2-6 alkenylsulfonyl group, a C2-6 alkynylsulfonyl group, a C1-6 alkylcarbonyl group, a C2-6 alkenylcarbonyl group and a C2-6 alkynylcarbonyl group, (10) a C1-6 alkylsulfonyl group, (11) a C2-6 alkenylsulfonyl group, (12) a C2-6 alkynylsulfonyl group, (13) a C1-6 alkylsulfinyl group, (14) a C2-6 alkenylsulfinyl group, (15) a C2-6 alkynylsulfinyl group, (16) a formyl group, (17) a C3-8 cycloalkyl group or a C3-8 cycloalkenyl group which may be optionally substituted respectively with one or more groups selected from the group consisting of hydroxy group, a halogen atom, nitrite group, a C1-6 alkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxy C1-6 alkyl group and an aralkyl group, (18) a 5- to 14-membered non-aromatic heterocyclic group which may be optionally substituted with one or more groups selected from the group consisting of hydroxy group, a halogen atom, nitrite group, a C1-6 alkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxy C1-6 alkyl group and an aralkyl group, (19) a C6-14 aromatic hydrocarbocyclic group which may be optionally substituted with one or more groups selected from the group consisting of hydroxy group, a halogen atom, nitrite group, a C1-6 alkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxy C1-6 alkyl group and an aralkyl group, and (20) a 5- to 14-membered aromatic heterocyclic group which may be optionally substituted with one or more groups selected from the group consisting of hydroxy group, a halogen atom, nitrite group, a C1-6 alkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxy C1-6 alkyl group and an aralkyl group.
4. A composition as claimed in claim 1, wherein the compound is one of more of:
3-(2-Cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one, 3-(2-fluoro-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one, 3-(2-cyanophenyl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one, 3-(2-cyanophenyl)-1-(3-pyridyl)-5-(2-pyrinidinyl)-1,2-dihydropyridin-2-one, 3-(2-fluoropyridin-3-yl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one, 3-(2-cyanopyridin-3-yl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one.
5. A composition comprising I) A compound represented by the following formula, a salt thereof or hydrates thereof:
Wherein A1a and A3a are the same as or different from each other and each indicates an optionally substituted C6-14 aromatic hydrocarbocyclic group or 5 to 14-membered aromatic heterocyclic group; and R indicates hydrogen atom or a halogen atom;
and II) an immunoregulatory, or an anti-inflammatory agent.
6. A composition, as claimed in any one of claims 1 to 5, further comprising a pharmaceutically acceptable carrier or excipient.
7. A composition, as claimed in any one of claims 1 to 6, wherein the immunoregulatory, or anti-inflammatory agent is an interferon, corticotrophin, glucocorticoid, cyclophosphamide, cyclosporine, azothioprine, mitoxantrone, a phosphodiesterase type IV inhibitor, a humanised monoclonal antibody against a leukocyte adhesion molecule, a synthetic polypeptide, a tissue matrix metalloproteinase (MMP) inhibitor or a tumour necrosis factor (TNF) inhibitor.
8. A composition, as claimed in claim 7, wherein the interferon is IFN, IFN-beta-1a, IFN-beta-1b, IFN-alpha-2a or IFN-alpha-2b.
9. A composition, as claimed in claim 8, wherein the IFN-beta-1a is Rebif or Avonex;
the IFN-beta-1b is Betaseron or Betaferon; the IFN-alpha-2a is Alphaferone; or IFN-alpha-2b is Viraferon.
10. A composition, as claimed in claim 7, wherein the humanised monoclonal antibody against a leukocyte adhesion molecule is Antegran.
11. A composition, as claimed in claim 7, wherein the synthetic polypeptide is glatiramer acetate or copolymer-1.
12. A composition, as claimed in claim 7, wherein the tissue matrix metalloproteinase (MMP) inhibitor is a hydroxamic acid-based inhibitor of MMPs.
13. A composition, as claimed in claim 7, wherein the tumour necrosis factor (TNF) inhibitor is Thalidomide or TNF-receptor immunoglobulin fusion protein.
14. A composition, as claimed in any one of claims 1 to 13, for use in the prevention or treatment of neurodegenerative disease.
15. A composition as claimed in claim 14 wherein the neurodegenerative disease is a demyelinating disorder.
16. The pharmaceutical composition according to claim 15, wherein the demyelinating disorder is encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Bane syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV-myelopathy, HTLV-myelopathy, progressive multifocal leucoencephalopathy, or a secondary demyelinating disorder.
17. A composition as claimed in claim 16, wherein the secondary demyelinating disease is CNS lupus erythematodes, polyarteritis nodosa, Sjoegren's syndrome, sarcoid granuloma isolated cerebral vasculitis.
18. Use of a compound as set out in any one of claims 1 to 5 and an immunoregulatory, or anti-inflammatory agent in the manufacture of a medicament for the prevention or treatment of acute or chronic neurodegenerative disease.
19. Use of a compound as set out in claim 18 wherein the neurodegenerative disease is a demyelinating disorder.
20. Use, as claimed in claim 18 or claim 19, wherein the compound and the immunoregulatory, or anti-inflammatory agent are administered separately, simultaneously or sequentially.
21. A method for the prevention or treatment of neurodegenerative disease, the method comprising administration to a patient, a composition as claimed in any one of claims 1 to 5.
22. A method as claimed in claim 21, wherein the neurodegenerative disease is a demyelinating disorder.
23. A method, as claimed in claim 21 or claim 22, wherein the compound and the immunoregulatory, or anti-inflammatory agent are administered separately, simultaneously or sequentially.
24. A kit comprising, a first container comprising a compound as set out in any one of claims 1 to 5 and a second container comprising an immunoregulatory, or anti-inflammatory agent optionally with instructions for use.
25. A kit, as claimed in claim 24, wherein one or both of the compounds as set out in any one of claims 1 to 5 and the immunoregulatory, or anti-inflammatory agent further comprise a pharmaceutically acceptable carrier or excipient.
26. A kit, as claimed in claim 24 or 25, for use in the prevention or treatment of a neurodegenerative disease.
27. A kit, as claimed in claim 26, wherein the neurodegenerative disease is a demyelinating disorder.
28. A kit, as claimed in any one of claims 24 to 27, wherein the compound and the immunoregulatory, or anti-inflammatory agent, are administered separately, simultaneously or sequentially.
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